Tumor Growth Rate as a Validated Early Radiological Biomarker Able to Reflect Treatment-Induced Changes in Neuroendocrine Tumors: The GREPONET-2 Study

Purpose: Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR(3m)) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET). Experimental Design: Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3 (perpendicular to 1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (Delta TGR(3m-BL); paired T test), and Aim-2: validate TGR(3m) (<0.8%/m vs. >= 0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox regression). Results: Of 785 patients screened, 127 were eligible. Mean (SD) TGR(0) and TGR(3m) were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) Delta TGR(3m-BL) paired-difference was -6.8%/m (19.3; P < 0.001). Most marked Delta TGR(3m-BL) [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); P = 0.0237] and chemotherapy [-7.9%/m (3.4); P = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31-16.52; P = 0.018) and low TGR(3m) (continuous variable; OR 1.09; 95% CI, 1.01-1.19; P = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade (P = 0.004) and stage (P = 0.017), TGR(3m) >= 0.8 (vs. <0.8) maintained its significance as a prognostic factor (P < 0.001), whereas TGR(0) and Delta TGR(3m-BL) did not. TGR(3m) >= 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21-3.70; P = 0.003)]. Conclusions: TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response.